Evans-Martin, S. | Search bioRxiv

bioRxiv2025

Grin2a Dysfunction Impairs Cognitive Flexibility by Disrupting LC Modulation of mPFC Circuits

Cognitive flexibility, a key executive function, is impaired in psychiatric disorders involving prefrontal cortical dysfunction. The medial prefrontal cortex (mPFC) regulates cognitive flexibility and receives noradrenergic input from the locus coeruleus (LC). Mutations in GRIN2A, encoding GluN2A-containing NMDA receptors, impair cognitive flexibility and psychiatric resilience, yet the circuit mechanisms remain unclear. Optogenetic LC[->]mPFC activation improved reversal learning in wild-type and Grin2a heterozygous (HET) mice but not in knockouts (KO), indicating a loss of noradrenergic modulation. Grin2a mutants displayed disrupted gamma and high-frequency oscillations (HFOs) in the mPFC. Exogenous norepinephrine failed to restore oscillatory activity, implicating 2-adrenoceptors in NE-driven cortical dynamics. Increased LC innervation and norepinephrine transporter (NET) expression in Grin2a mutants suggest excessive noradrenergic input and impaired NE clearance. These findings identify GluN2A as essential for LC-driven prefrontal network synchronization and cognitive flexibility, offering insights into NE dysfunction in psychiatric disorders.

neuroscience↗

bioRxiv2024

Grin2a Ablation Distinctly Reshapes PV+ and SST+ Interneuron circuits in the Medial Prefrontal Cortex to Amplify Gamma Oscillations

Schizophrenia (SCZ) is a debilitating mental health disorder marked by cognitive deficits, especially in executive functions, which are often resistant to treatment. The GRIN2A gene encodes the GluN2A subunit of N-methyl-D-aspartate (NMDA) receptor. Rare coding mutations in GRIN2A, such as protein-truncating variants, increase susceptibility to SCZ by [~]20-fold. However, the effects on network dynamics and the function of GABAergic interneurons (INs) in the medial prefrontal cortex (mPFC) remain unclear. In this study, we use brain slices from Grin2a mutant mice to investigate inhibitory synaptic and oscillatory activity driven by parvalbumin-positive (PV+) and somatostatin-positive (SST+) INs. Our findings reveal significant alterations in synaptic currents and inhibitory modulation arise from GluN2A deficiency. Specifically, both heterozygous and knockout Grin2a mutants exhibit impaired synaptic transmission and release properties of INs inputs, including changes in release probability and evoked quantal events to layer V pyramidal neurons. Genotype-dependent alterations were observed in the frequency, kinetics, and amplitude of excitatory and inhibitory postsynaptic currents. Immunohistochemical analysis showed an increased density of PV+ and SST+ INs in the Grin2a mutants, consistent with an overall increase in inhibitory tone. Additionally, optogenetic stimulation revealed a dynamic shift for inducing gamma-band oscillations through PV+ INs. Overall, our study highlights the essential role of GluN2A-containing NMDA receptors in modulating inhibitory tone and maintaining network stability in the mPFC of adult mice and elucidates a pathophysiological mechanism that might contribute to cognitive deficits often observed in SCZ patients.

neuroscience↗